Cytokine profiles in dengue fever and dengue hemorrhagic fever: A study from Indonesia.

Recent studies have demonstrated that cytokine dysregulation has a critical role in the pathogenesis of dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). The aim of this study was to investigate the association between tumor necrosis factor (TNF- α), interleukin 6 (IL-6), interleukin 10 (IL-10), and interleukin 17 (IL-17) with infection status, and severity of dengue. A prospective cross-sectional study was conducted at three hospitals in Gianyar regency and Denpasar municipality, Bali, Indonesia, from June to December 2022. Sixty-four dengue infected patients were involved. Patients' serum was tested for dengue infection using NS1 antigen rapid test, dengue virus immunoglobulin M (IgM) and immunoglobulin G (IgG) test, and reverse transcription polymerase chain reaction (RT-PCR). Cytokine levels (TNF-α, IL-6, IL-10, and IL-17) were measured using enzyme-linked immunosorbent assay (ELISA). Infection status was determined by combining serological and RT-PCR results, categorizing patients into primary and secondary infections. The present study found that DF patients had lower TNF-α, IL-6, and IL-17 but higher IL-10 levels compared to DHF patients (p<0.001). Elevated TNF-α, IL-6, and IL-17 levels were higher in secondary infection, while IL-10 level was higher in primary infection (p<0.001). In conclusion, cytokines play a crucial role in the interplay between cytokine dysregulation and dengue infection dynamics.

Evaluation of clinical and laboratory characteristics of dengue viral infection and risk factors of dengue hemorrhagic fever: a multi-center retrospective analysis.

BACKGROUND: Dengue Viral Infection (DVI) has become endemic in Pakistan since the first major outbreak in Karachi in 1996. Despite aggressive measures taken by relevant authorities, Pakistan has been dealing with a worsening dengue crisis for the past two decades. DHF is severe form of dengue infection which is linked with significant morbidity and mortality. Early identification of severe dengue infections can reduce the morbidity and mortality. In this context we planned current study in which we find out the different factors related with DHF as well as clinical laboratory features of DHF and compare them to DF so that patients can be best evaluated for DHF and managed accordingly at admission. METHODS: Retrospective study conducted over a period of 6 years (2013-2018) in two tertiary care hospitals in Pakistan. Data were collected by using a pre-structured data collection form. Data were statistically analyzed to determine the clinical and laboratory characteristics of DVI and risk factors of dengue hemorrhagic fever (DHF). RESULTS: A total 512 dengue cases (34.05 ± 15.08 years; Male 69.53%) were reviewed. Most common clinical manifestations of DVI were fever (99.60%), headache (89.1%), chills (86.5%), rigors (86.5%), myalgia (72.3%). Less common clinical manifestations were vomiting (52.5%), arthralgia (50.2%) and skin rashes (47.5%). Furthermore, nasal bleeding (44.1%), gum bleeding (32.6%), pleural effusion (13.9%) and hematuria (13.1%) were more profound clinical presentations among DHF patients. Mortality rate was 1.5% in this study. Logistic regression analysis indicated that delayed hospitalization (OR: 2.30) and diabetes mellitus (OR:2.71), shortness of breath (OR:2.21), association with risk groups i.e., living near stagnant water, travelling to endemic areas, living in endemic regions (OR:1.95), and presence of warning signs (OR:2.18) were identified as risk factors of DHF. Statistically we found that there is strong association of diabetes mellitus (DM) with DHF while the patient suffering from DM individually had higher odds (2.71) of developing DHF than patients without disease. CONCLUSIONS: The current study demonstrated that the clinical and laboratory profiles of DF and DHF are significantly distinct. Significant predictors of DHF were advanced age, diabetes mellitus, ascites, pleural effusion, thick gallbladder and delayed hospitalization. The identification of these factors at early stage provides opportunities for the clinicians to identify high risk patients and to reduce dengue-related morbidity and mortality.

Dengue virus serotypes and related factors in children with dengue hemorrhagic fever in Southern Vietnam.

INTRODUCTION: After the Coronavirus Disease 2019 pandemic, a high number of cases and severe dengue in children were reported in some provinces in the south of Vietnam. This study aimed to determine the distribution of dengue virus serotypes and their correlation with demographic factors, disease severity, clinical manifestations, and laboratory findings. METHODOLOGY: This study employed a cross-sectional design. Ninety-six dengue-infected children admitted to Can Tho Children's Hospital between October 2022 and March 2023 were included. Confirmation of dengue infection was achieved through the real-time polymerase chain reaction (RT-PCR). RESULTS: Among the identified serotypes, DENV-2 accounted for the highest proportion (71.87%), followed by DENV-1 (23.96%), and DENV-4 (4.17%). DENV-3 was not detected. No significant demographic, disease severity, or laboratory differences were observed among the identified dengue serotypes. However, DENV-2 was associated with a higher occurrence of mucous membrane hemorrhages and gastrointestinal bleeding compared to other serotypes. CONCLUSIONS: Although DENV-2 was the most prevalent serotype responsible for dengue in children in southern Vietnam, it did not lead to more severe cases compared to other serotypes. This finding is crucial for evaluating the illness's prognosis.

Relationship between the Number of Repeats in the Neck Regions of L-SIGN and Augmented Virus Replication and Immune Responses in Dengue Hemorrhagic Fever.

C-type lectins play a crucial role as pathogen-recognition receptors for the dengue virus, which is responsible for causing both dengue fever (DF) and dengue hemorrhagic fever (DHF). DHF is a serious illness caused by the dengue virus, which exists in four different serotypes: DEN-1, DEN-2, DEN-3, and DEN-4. We conducted a genetic association study, during a significant DEN-2 outbreak in southern Taiwan, to explore how variations in the neck-region length of L-SIGN (also known as CD209L, CD299, or CLEC4M) impact the severity of dengue infection. PCR genotyping was utilized to identify polymorphisms in variable-number tandem repeats. We constructed L-SIGN variants containing either 7- or 9-tandem repeats and transfected these constructs into K562 and U937 cells, and cytokine and chemokine levels were evaluated using enzyme-linked immunosorbent assays (ELISAs) following DEN-2 virus infection. The L-SIGN allele 9 was observed to correlate with a heightened risk of developing DHF. Subsequent results revealed that the 9-tandem repeat was linked to elevated viral load alongside predominant T-helper 2 (Th2) cell responses (IL-4 and IL-10) in K562 and U937 cells. Transfecting K562 cells in vitro with L-SIGN variants containing 7- and 9-tandem repeats confirmed that the 9-tandem repeat transfectants facilitated a higher dengue viral load accompanied by increased cytokine production (MCP-1, IL-6, and IL-8). Considering the higher prevalence of DHF and an increased frequency of the L-SIGN neck's 9-tandem repeat in the Taiwanese population, individuals with the 9-tandem repeat may necessitate more stringent protection against mosquito bites during dengue outbreaks in Taiwan.

The alteration of NK cells phenotypes related to the functions and dengue disease outcomes.

Natural killer cells (NK cells) are the front line of immune cells to combat pathogens and able to influence the subsequent adaptive immune responses. One of the factors contributing to pathogenesis in dengue hemorrhagic fever (DHF) disease is aberrant immune activation during early phase of infection. This study explored the profile of NK cells in dengue infected pediatric patients with different degrees of disease severity. DHF patients contained higher frequency of activated NK cells but lower ratio of CD56dim:CD56bright NK subsets. Activated NK cells exhibited alterations in several NK receptors. Interestingly, the frequencies of NKp30 expressing activated NK cells were more pronounced in dengue fever (DF) than in DHF pediatric patients. In vitro functional analysis indicated that degranulation of NK cells in responding to dengue infected dendritic cells (DCs) required cell-cell contact and type I IFNs. Meanwhile, Interferon gamma (IFN-γ) production initially required cell-cell contact and type I IFNs followed by Interleukin-12 (IL-12), Interleukin-15 (IL-15) and Interleukin-18 (IL-18) resulting in the amplification of IFN-γ producing NK cells over time. This study highlighted the complexity and the factors influencing NK cells responses to dengue virus. Degree of activation, phenotypes of activated cells and the crosstalk between NK cells and other immune cells, could modulate the outcome of NK cells function in the dengue disease.

Retrospective Analysis of Severe Dengue by Dengue Virus Serotypes in a Population with Social Security, Mexico 2023.

BACKGROUND: Risk factors for severe dengue manifestations have been attributed to various factors, including specific serotypes, sex, and age. Mexico has seen the re-emergence of DENV-3, which has not circulated in a decade. OBJECTIVE: To describe dengue serotypes by age, sex, and their association with disease severity in dengue-positive serum samples from epidemiological surveillance system units. MATERIALS AND METHODS: A descriptive analysis was conducted to evaluate the frequency of dengue severity by sex, age, disease quarter, geographical location, and dengue virus serotypes. The study was conducted using laboratory samples from confirmed dengue cases through RT-qPCR from the epidemiological surveillance laboratory network of the Mexican Social Security Institute, Mexico. Simple frequencies and proportions were calculated using the z-test for proportional differences between groups. Bivariate analysis with adjusted Chi2 was performed, and binary logistic regression models were constructed using the forward Wald method considering the model's predictive capacity. The measure of association was the odds ratio, with 95% confidence intervals. Statistical significance was set to an alpha level of <0.05. RESULTS: In 2023, 10,441 samples were processed for dengue RT-qPCR at the IMSS, with a predominance of serotype DENV-3 (64.4%). The samples were mostly from women (52.0%) and outpatient cases (63.3%). The distribution of dengue severity showed significant variations by age, with a lower proportion of severe cases in young children and a higher proportion in the 5- to 14-year-old group. Hospitalizations increased significantly with severity. Warm regions had more cases overall and severity. Cases were most frequent from July to September. While DENV-2 was associated with severity, DENV-4 was not. Binary regression identified higher risk in women, age extremes, and DENV-2, with an overall predictive model of 58.5%. CONCLUSIONS: Women, age groups at the extremes of life, and the DENV-2 serotype presented severe risk of dengue in a population with social security in Mexico during 2023.

Analysis of signs and symptoms in confirmed cases of severe dengue among children aged 0 to 10 years old.

OBJECTIVE: The prevalent symptoms of severe dengue in pediatric patients are divided into three subgroups: severe plasma leakage, severe bleeding, and severe organ damage. In addition, the seasonal patterns of the disease and the outcomes of cure or death from dengue were evaluated. METHODS: An epidemiological, observational, analytical, cross-sectional study was conducted with data from the Notifiable Disease Information System (SINAN - Sistema de Informação de Agravos de Notificação and DATASUS - Departamento de Informática do Sistema Único de Saúde) of the Ministry of Health from 2019 to 2020. RESULTS: During the study period, 1,857 cases of severe dengue were observed in the pediatric age group, with the most common symptoms being respiratory failure, melena, hematemesis, and altered level of consciousness. The total proportion of patients hospitalized for severe dengue was 89.6%, and 51.2% of these patients died, corroborating the importance of early detection of the disease. CONCLUSION: Severe dengue is more prevalent during the seasonal period, with hot and humid characteristics owing to the mechanism involved in the viral cycle. The most prevalent symptoms of severe dengue in pediatric patients were respiratory failure alone, gastrointestinal bleeding, and altered level of consciousness. It is important to identify signs of severity for early intervention and a better prognosis, considering that death is closely related to a delayed diagnosis.

Genotype of dengue virus serotype 1 in relation to severe dengue in Guangzhou, China.

Guangzhou has been the city most affected by the dengue virus (DENV) in China, with a predominance of DENV serotype 1 (DENV-1). Viral factors such as dengue serotype and genotype are associated with severe dengue (SD). However, none of the studies have investigated the relationship between DENV-1 genotypes and SD. To understand the association between DENV-1 genotypes and SD, the clinical manifestations of patients infected with different genotypes were investigated. A total of 122 patients with confirmed DENV-1 genotype infection were recruited for this study. The clinical manifestations, laboratory tests, and levels of inflammatory mediator factors were statistically analyzed to investigate the characteristics of clinical manifestations and immune response on the DENV-1 genotype. In the case of DENV-1 infection, the incidence of SD with genotype V infection was significantly higher than that with genotype I infection. Meanwhile, patients infected with genotype V were more common in ostealgia and bleeding significantly. In addition, levels of inflammatory mediator factors including IFN-γ, TNF-α, IL-10, and soluble vascular cell adhesion molecule 1 were higher in patients with SD infected with genotype V. Meanwhile, the concentrations of regulated upon activation normal T-cell expressed and secreted and growth-related gene alpha were lower in patients with SD infected with genotype V. The higher incidence of SD in patients infected with DENV-1 genotype V may be attributed to elevated cytokines and adhesion molecules, along with decreased chemokines.

Prognostic values of serum lactate-to-bicarbonate ratio and lactate for predicting 28-day in-hospital mortality in children with dengue shock syndrome.

This study aimed to assess the clinical utility of blood lactate-to-bicarbonate (L/B) ratio, as a prognostic factor for 28-day in-hospital mortality in children with dengue shock syndrome (DSS), admitted to the pediatric intensive care unit (PICU). This single-center retrospective study was conducted at a tertiary children hospital in southern Vietnam from 2013 to mid-2022. Prognostic models for DSS mortality were developed, using a predefined set of covariates in the first 24 hours of PICU admission. Area under the curves (AUCs), multivariable logistic and Least Absolute Shrinkage and Selection Operator (LASSO) regressions, bootstrapping and calibration slope were performed. A total of 492 children with DSS and complete clinical and biomarker data were included in the analysis, and 26 (5.3%) patients died. The predictive values for DSS mortality, regarding lactate showing AUC 0.876 (95% CI, 0.807-0.944), and that of L/B ratio 0.867 (95% CI, 0.80-0.934) (P values of both biomarkers < .001). The optimal cutoff point of the L/B ratio was 0.25, while that of lactate was 4.2 mmol/L. The multivariable model showed significant clinical predictors of DSS fatality including severe bleeding, cumulative amount of fluid infused and vasoactive-inotropic score (>30) in the first 24 hours of PICU admission. Combined with the identified clinical predictors, the L/B ratio yielded higher prognostic values (odds ratio [OR] = 8.66, 95% confidence interval [CI], 1.96-38.3; P < .01) than the lactate-based model (OR = 1.35, 95% CI, 1.15-1.58; P < .001). Both the L/B and lactate models showed similarly good performances. Considering that the L/B ratio has a better prognostic value than the lactate model, it may be considered a potential prognostic biomarker in clinical use for predicting 28-day mortality in PICU-admitted children with DSS.

Endothelial and inflammatory pathophysiology in dengue shock: New insights from a prospective cohort study in Vietnam.

Dengue shock (DS) is the most severe complication of dengue infection; endothelial hyperpermeability leads to profound plasma leakage, hypovolaemia and extravascular fluid accumulation. At present, the only treatment is supportive with intravenous fluid, but targeted endothelial stabilising therapies and host immune modulators are needed. With the aim of prioritising potential therapeutics, we conducted a prospective observational study of adults (≥16 years) with DS in Vietnam from 2019-2022, comparing the pathophysiology underlying circulatory failure with patients with septic shock (SS), and investigating the association of biomarkers with clinical severity (SOFA score, ICU admission, mortality) and pulmonary vascular leak (daily lung ultrasound for interstitial and pleural fluid). Plasma was collected at enrolment, 48 hours later and hospital discharge. We measured biomarkers of inflammation (IL-6, ferritin), endothelial activation (Ang-1, Ang-2, sTie-2, VCAM-1) and endothelial glycocalyx breakdown (hyaluronan, heparan sulfate, endocan, syndecan-1). We enrolled 135 patients with DS (median age 26, median SOFA score 7, 34 required ICU admission, 5 deaths), together with 37 patients with SS and 25 healthy controls. Within the DS group, IL-6 and ferritin were associated with admission SOFA score (IL-6: ßeta0.70, p<0.001 & ferritin: ßeta0.45, p<0.001), ICU admission (IL-6: OR 2.6, p<0.001 & ferritin: OR 1.55, p<0.001) and mortality (IL-6: OR 4.49, p = 0.005 & ferritin: OR 13.8, p = 0.02); both biomarkers discriminated survivors and non-survivors at 48 hours and all patients who died from DS had pre-mortem ferritin ≥100,000ng/ml. IL-6 most strongly correlated with severity of pulmonary vascular leakage (R = 0.41, p<0.001). Ang-2 correlated with pulmonary vascular leak (R = 0.33, p<0.001) and associated with SOFA score (ß 0.81, p<0.001) and mortality (OR 8.06, p = 0.002). Ang-1 was associated with ICU admission (OR 1.6, p = 0.005) and mortality (OR 3.62, p = 0.006). All 4 glycocalyx biomarkers were positively associated with SOFA score, but only syndecan-1 was associated with ICU admission (OR 2.02, p<0.001) and mortality (OR 6.51, p<0.001). This study highlights the central role of hyperinflammation in determining outcomes from DS; the data suggest that anti-IL-1 and anti-IL-6 immune modulators and Tie2 agonists may be considered as candidates for therapeutic trials in severe dengue.

Genetic variants associated with dengue hemorrhagic fever. A systematic review and meta-analysis.

Dengue hemorrhagic fever (DHF) is a severe condition resulting from the dengue virus, with four serotypes known as DEN-1, DEN-2, DEN-3, and DEN-4. Genetic variations play a crucial role in influencing susceptibility to DHF. Therefore, this investigation conducted a meta-analysis to uncover genetic changes that might have remained undetected in individual studies due to small sample sizes or methodological differences. Among 2212 initially identified studies, 23 were deemed suitable for analysis based on PRISMA guidelines. Toll-like receptors (TLR) and CD209 showed significant association with DHF (odds ratios: TLR=0.56, CD209 =0.55), indicating protective effects. However, tumor necrosis factor (TNF) and human leukocyte antigen (HLA) did not exhibit a statistically significant relationship with DHF. This study emphasizes the relevance of TLR and CD209 in DHF susceptibility and resistance across diverse geographical locations.

Severe disease during both primary and secondary dengue virus infections in pediatric populations.

Dengue is a global epidemic causing over 100 million cases annually. The clinical symptoms range from mild fever to severe hemorrhage and shock, including some fatalities. The current paradigm is that these severe dengue cases occur mostly during secondary infections due to antibody-dependent enhancement after infection with a different dengue virus serotype. India has the highest dengue burden worldwide, but little is known about disease severity and its association with primary and secondary dengue infections. To address this issue, we examined 619 children with febrile dengue-confirmed infection from three hospitals in different regions of India. We classified primary and secondary infections based on IgM:IgG ratios using a dengue-specific enzyme-linked immunosorbent assay according to the World Health Organization guidelines. We found that primary dengue infections accounted for more than half of total clinical cases (344 of 619), severe dengue cases (112 of 202) and fatalities (5 of 7). Consistent with the classification based on binding antibody data, dengue neutralizing antibody titers were also significantly lower in primary infections compared to secondary infections (P ≤ 0.0001). Our findings question the currently widely held belief that severe dengue is associated predominantly with secondary infections and emphasizes the importance of developing vaccines or treatments to protect dengue-naive populations.

Harness risk stratification of diabetic patients with dengue in a cohort study.

BACKGROUND: Identifying predictors of severe dengue (SD) is key for triage and management of patients as well as for advising travellers to countries where dengue is endemic. In this, meta-analyses have raised diabetes mellitus as a risk factor for SD and a prognostic factor for dengue-related mortality. The purpose of this study was to assess whether diabetic patients (DPs) are at increased risk for SD in comparison to non-diabetic patients (NDPs) in a setting of high prevalence of type 2 diabetes mellitus and increasing endemicity for dengue. METHODS: In a cohort study conducted during the 2019 dengue epidemic on Reunion Island, we estimated the risk ratios (RR) of DPs for SD (WHO 2009 definition), hospitalisation, intensive care unit (ICU) admission, critical care need or death in the ICU, and scales rating severity or multiple organ dysfunction syndrome (MODS), among confirmed cases of dengue (positive RT-PCR or NS1 antigen). RESULTS: In a Poisson regression model adjusted for age, gender and comorbidity, DPs were more likely to develop SD (adjusted RR: 1.46, 95%CI 1.10-1.95), to be hospitalised, admitted to the ICU, and need critical care or die in the ICU. Subgroup analyses identified female DPs, non-elderly DPs (< 65 years) and DPs with low Charlson score (< 3) to be at higher risk for SD, the two first subgroups trough more severe presentation (higher Simplified Acute Physiology Score-2 values; higher MODS scores, respectively). Male gender, age less than 65 years and mixed comorbidity were identified as prognostic factors for critical care need or death in the ICU, male and non-elderly DPs being more likely to develop MODS than their non-diabetic counterparts. CONCLUSIONS: Together, these data highlight the role of diabetes mellitus in the progression from dengue to SD through higher severity per se or the event of MODS.

Effect of montelukast in preventing dengue with warning signs among patients with dengue: A multicenter, randomized, double-blind, placebo-controlled trial.

BACKGROUND: Montelukast has shown potential as a candidate treatment for dengue. This study aimed to evaluate the efficacy and safety of montelukast in preventing dengue with warning signs. METHODS: This multicenter, randomized, double-blind, placebo-controlled trial enrolled adult participants with NS1 antigenemia in Thailand. The participants were randomly assigned to receive either oral montelukast (10 mg) or a placebo for 10 days or until all symptoms resolved. RESULTS: Between January 2021 and June 2023, 358 participants were enrolled and randomly assigned (1:1) to receive either montelukast or placebo. The incidence rate of warning signs in the montelukast group and the placebo group were 9.5% and 7.8% per day, respectively. There was no difference between the two groups (HR 1.36; 95%CI 0.94-1.96, P = 0.105). No statistically significant differences were observed in the incidence rate of severe dengue, hemoconcentration, thrombocytopenia, admission, or recovery from dengue. Neither dengue shock, nor mortality occurred. The montelukast group exhibited a decreased incidence rate of transaminase elevations (0.7% vs 1.4% per day, HR: 0.48, 95%CI 0.25-0.90, P = 0.023). CONCLUSION: Oral montelukast does not reduce the incidence of warning signs among patients with dengue. Nevertheless, the observed decrease in transaminase elevations warrants further investigation to evaluate the potential effect of montelukast. CLINICAL TRIALS REGISTRATION: Clinicaltrials.gov, NCT04673422, registered on 9 December 2020.

Spectrum of Liver Injury in Dengue Fever: Cause or Effect of Severe Dengue?

The study aimed to determine if deranged liver function tests (LFTs) can predict severe dengue or mortality. It included 135 dengue patients, with a mean age of 30.9 ± 12.09 years. Among the patients, 82 (60.7%) were under 30 years of age. Nearly half of the patients (64, 47. 4%) had some degree of liver damage indicated by deranged LFTs, 27 (42.1%) had elevated alanine transaminase (ALT), 7 (10.9%) had increased bilirubin, and 30 (46.9%) had high values of alkaline phosphatase (ALP). However, only elevated ALP levels were positively correlated with mortality (Pearson's R = 0.282, p = <0.05). The mean bilirubin was 11.711 ± 8.602 umol/l, and the mean values of ALT and ALP were 107 ± 240 and 113.571 ± 59.91 IU/L, respectively, which were higher than the normal. The study findings suggested that hepatic derangement is a common occurrence in dengue patients, and increased ALP levels could be an indicator of a higher risk of mortality. These findings can help improve patient care by identifying the potential risk factors for mortality. Key Words: Dengue, Liver function tests, Alanine transaminase, Alkaline phosphatase.

Peptide-ligand conjugate based immunotherapeutic approach for targeted dismissal of non-structural protein 1 of dengue virus: A novel therapeutic solution for mild and severe dengue infections.

Dengue virus infection has significantly increased, with reported cases soaring from 505,430 in 2000 to 2,809,818 in 2022, emphasizing the need for effective treatments. Among the eleven structural and non-structural proteins of DENV, Non-structural protein 1 (NS1) has emerged as a promising target due to its diverse role in modulating the immune response, inducing vascular leakage, and facilitating viral replication and assembly. Monoclonal antibodies are the sole therapeutics to target NS1, but concerns about their cross-reactivity persist. Given these concerns, our study focuses on designing a novel Peptide Ligand Conjugate (PLC) as a potential alternative immunotherapeutic agent against NS1. This PLC aims to mediate the immune elimination of soluble NS1 and NS1-presenting DENV-infected host cells by pre-existing vaccine-induced immunity. By employing the High Throughput Virtual Screening (HTVS) method, QikProp analysis, and Molecular Dynamics studies, we identified three hits from Asinex Biodesigned Ligands out of 220,177 compounds that show strong binding affinity towards the monoclonal binding site of NS1 protein. After a rigorous analysis of physicochemical characteristics, antigenicity, allergenicity, and toxicity using various servers, we selected two peptides: the minimum epitopic region of the Diphtheria and Tetanus toxins as the peptide components of the PLCs. A non-cleavable, non-reactive oxime linker connected the ligand with the peptide through oxime and amide bonds. DPT vaccine is widely used in dengue-endemic countries, and it has been reported that antibodies titer against MER of Diphtheria toxin and Tetanus toxins persist lifelong in DPT-vaccinated people. Therefore, once the rationally designed PLCs bind to NS1 through the ligands, the peptide will induce an immune response against NS1 by triggering pre-existing DPT antibodies and activating memory cells. This orchestrated immune response will destroy soluble NS1 and NS1-expressing DENV-infected cells, thereby reducing the illness of severe dengue hemorrhagic fever and the DENV infection, respectively. Given the increasing demand for new therapeutics for DENV treatment, further investigation into this novel immune-therapeutic strategy may offer a new avenue for treating mild and severe dengue infections.

Artificial Intelligence Approach for Severe Dengue Early Warning System.

Dengue fever is a viral infectious disease transmitted through mosquito bites, and has symptoms ranging from mild flu-like symptoms to deadly complications. Dengue fever is one of the global burden diseases which annually have 50-100 million cases with 500,000 cases of severe dengue fever, of which 22,000 deaths occur mostly in children. Despite the discovery of vaccines, vector control is still the main approach for prevention efforts. Early detection and accessibility to medical care can reduce severe Dengue mortality rate from 50% to 2%. In the previous study, both statistical and machine learning methods have the potential for predicting a Dengue outbreak, but the study is still fragmented and limited on implementing the generated model into an early warning system application. In this study, we developed an artificial intelligence model with spatiotemporal to predict Dengue outbreak and Dengue incidence case which is ready to be implemented into an early warning system application. Indonesia, especially Semarang City, has experienced an endemic Dengue. We used Semarang City spatiotemporal, meteorological, climatological, and Dengue surveillance epidemiology data from January 2014 to December 2021 in 16 districts of Semarang City. We reviewed 7208 samples from 16 districts and 1 city per week during 8 years. The entire dataset was divided into training (80%) and testing (20%) to develop a prediction model. We used machine learning and Long Short Term Memory (LSTM) to predict Dengue outbreak 1 week before the event for each district. and machine learning to predict Dengue incident cases 1 week before the event for each district. Accuracy, area under the receiver operating characteristic curve (AUROC), precision, recall, and F1 score were considered to evaluate the Dengue outbreak prediction model. The Dengue incidence cases prediction model will evaluate using Mean Squared Error (MSE), Mean Absolute Error (MAE), Root Mean Squared Error (RMSE), and R-Squared (R2). Extra Trees Classifier model shown outperform in Dengue outbreak prediction, with accuracy 0.8925, AUROC 0. 9529, Recall 0.6117, precision 0.8880, and F1 score 0.7238. CatBoost Regressor model is shown to outperform in Dengue incidence cases prediction, with R2 0.5621, MAE 0.6304, MSE 1.1997, and RMSE 1.0891. The study proves that Artificial Intelligence (AI) with a spatiotemporal approach can give higher performance in Dengue outbreak and incidence cases prediction. Utilization of AI approaches that are sensitive with spatiotemporal feasibility to implement in Dengue early warning system application may contribute to increase the policy makers and community attention to do accurate community-based vector control.

Risk factors associated with severe dengue in Latin America: A systematic review and meta-analysis.

OBJECTIVE: Severe dengue is a significant health problem in Latin America, with children being the most affected. Understanding risk factors for severe dengue is crucial for enhancing patient care. Therefore, this study aims to systematically review the literature to identify the risk factors associated with severe dengue in Latin America through systematic review and meta-analysis. METHODS: PubMed, SciELO, LILACS and EMBASE databases were used to search for eligible scientific articles for the review. The outcomes considered were symptoms of severe dengue, hospitalisation and death. The Joanna Briggs Institute Critical Appraisal Checklist was used to assess the quality of the studies. Data analysis was performed using STATA v 13.0 software. The degree of heterogeneity between studies was quantified using the I2 measure, and statistically significant results were defined as those with p values <0.05. RESULTS: Of the 1876 articles screened, 47 articles were included in the systematic review and 45 articles were analysed through meta-analysis. Identified risk factors associated with severe dengue included secondary dengue infection, female sex, white or Caucasian ethnicity and specific signs and symptoms such as headache, myalgia and/or arthralgia, vomiting/nausea, abdominal pain or tenderness, diarrhoea, prostration, lethargy, fatigue or similar. For the death outcome, respiratory symptoms and age <18 years were identified as risk factors. On the other hand, in women, the diagnosis of positive tourniquet test, platelet count <100,000 per µL and symptoms of capillary fragility were associated with a lower probability of death. These data highlight the importance of early screening of patients, to identify possible haemorrhagic signs and reduce deaths from dengue. This study has limitations, including possible publication bias, heterogeneity of results and study design biases. CONCLUSION: These findings are significant for shaping strategies, management approaches and identifying high-risk groups, which will help establish future guidelines.

Markers of prolonged hospitalisation in severe dengue.

BACKGROUND: Dengue is one of the most common diseases in the tropics and subtropics. Whilst mortality is a rare event when adequate supportive care can be provided, a large number of patients get hospitalised with dengue every year that places a heavy burden on local health systems. A better understanding of the support required at the time of hospitalisation is therefore of critical importance for healthcare planning, especially when resources are limited during major outbreaks. METHODS: Here we performed a retrospective analysis of clinical data from over 1500 individuals hospitalised with dengue in Vietnam between 2017 and 2019. Using a broad panel of potential biomarkers, we sought to evaluate robust predictors of prolonged hospitalisation periods. RESULTS: Our analyses revealed a lead-time bias, whereby early admission to hospital correlates with longer hospital stays - irrespective of disease severity. Importantly, taking into account the symptom duration prior to hospitalisation significantly affects observed associations between hospitalisation length and previously reported risk markers of prolonged stays, which themselves showed marked inter-annual variations. Once corrected for symptom duration, age, temperature at admission and elevated neutrophil-to-lymphocyte ratio were found predictive of longer hospitalisation periods. CONCLUSION: This study demonstrates that the time since dengue symptom onset is one of the most significant predictors for the length of hospital stays, independent of the assigned severity score. Pre-hospital symptom durations need to be accounted for to evaluate clinically relevant biomarkers of dengue hospitalisation trajectories.

A curious case of expanded dengue syndrome.

Dengue fever (DF) primarily presents with fever, headache, malaise, bleeding manifestations and haemoconcentration. World Health Organization (WHO) classifies DF according to levels of severity: (a) without warning signs; (b) with warning signs, such as abdominal pain, persistent vomiting, fluid accumulation, mucosal bleeding, lethargy, liver enlargement, increasing haematocrit and thrombocytopenia; and (c) severe dengue with severe plasma leakage, severe bleeding or organ failure. Atypical clinical presentations of DF are defined as expanded dengue syndrome: this includes renal, cardiac, hepatic or cerebral damage. We report such a severe case where a young man developed acute kidney injury, acute fulminant liver failure and acute pancreatitis secondary to DF, but recovered.